More than fifty years after the commercialization of the Ventolin metered-dose inhaler (MDI), its constituent active ingredient, salbutamol sulfate (SS), remains the most prescribed short-acting beta agonist for the first-line treatment of acute asthma attacks and the metered-dose inhaler remains its primary dosage form. The first generation of Ventolin MDI was developed at a time when environmental and regulatory concerns were less stringent than today. The MDI industry is now on the verge of a second major reformulation effort in response to environmental concerns. This paper serves to illustrate how modern computational modeling of molecular interactions can aid the reformulation process. By way of a case study, computational modeling was performed to compare poly(ethylene glycol) 400 (PEG400) and, separately, isopropyl myristate (IPM) as substitutes for the ethanol used in some generic salbutamol sulfate suspension-based hydrofluoroalkane MDIs.

PEG400 and IPM were investigated as potential alternative cosolvents to ethanol in HFA134a-based SS suspension MDI formulations. Density functional theory (DFT) molecular dynamics simulations were used to evaluate the compatibility of the candidate cosolvents with the formulation's components. Corresponding physical formulations were filled into polyethylene terephthalate (PET) and, separately, aluminium canisters. In-vitro pharmaceutical product performance and macroscopic visual appearance were assessed and compared to the results of the simulation studies.

The simulation studies indicated that PEG400 would be a good candidate as a replacement for ethanol whereas IPM would not. The in-vitro and visual assessments support the predicted outcome of the simulation studies.

This work suggests that molecular dynamics simulations may provide a useful tool to aid the selection of compatible excipients when reformulating MDI suspension-based products, thereby reducing the time and cost associated with manufacturing and testing of physical samples.